Cholesteryl Ester Transfer Protein

Introduction

Cholesteryl ester transfer protein (CETP) is a plasma protein that plays a central role in human lipid metabolism. It facilitates the transfer of cholesteryl esters from high-density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins, such as very-low-density lipoprotein (VLDL) and low-density lipoprotein (LDL), in exchange for triglycerides. This process significantly influences the levels of various lipoproteins in the blood, particularly HDL cholesterol, often referred to as “good cholesterol” due to its association with cardiovascular health.

Biological Basis

The CETPgene encodes a hydrophobic glycoprotein that is secreted into the plasma. Its primary biological function is to mediate the movement of lipids between different lipoprotein classes. By transferring cholesteryl esters from HDL to other lipoproteins,CETPis involved in the reverse cholesterol transport pathway, which is the process by which excess cholesterol is removed from peripheral tissues and returned to the liver for excretion. Genetic variations, such as single nucleotide polymorphisms (SNPs) within theCETPgene, can affect the protein’s activity, leading to alterations in plasma lipid profiles. For instance, specific SNPs inCETP have been associated with varying levels of HDL cholesterol.^[1] Studies have identified variants like rs3764261 , rs1864163 , and rs9989419 as having associations with HDL cholesterol concentrations.^[1] These genetic differences contribute to the observed variability in lipid levels among individuals.^[2]

Clinical Relevance

Variations in CETPactivity and gene polymorphisms are clinically relevant due to their impact on lipoprotein levels, which are key risk factors for cardiovascular diseases. Higher HDL cholesterol levels are generally considered protective against conditions like coronary artery disease (CAD).^[3] Consequently, genetic variants that lead to reduced CETP activity often result in elevated HDL cholesterol, a phenotype that has been hypothesized to confer protection against CAD.^[3] Genome-wide association studies (GWAS) have consistently highlighted the CETP locus as a significant determinant of lipid concentrations, including HDL cholesterol.^{[1], [2], [4]} Understanding the genetic influences on CETPcan therefore provide insights into an individual’s predisposition to dyslipidemia and related cardiovascular risks.

Social Importance

Cardiovascular diseases remain a leading cause of morbidity and mortality worldwide, posing a substantial public health burden. Genetic research into proteins likeCETPcontributes to a deeper understanding of the complex interplay between genes, environment, and disease risk. Identifying genetic markers inCETPthat influence lipid profiles can aid in developing more personalized approaches to risk assessment and prevention strategies for cardiovascular disease. This knowledge also informs pharmaceutical research, as modulatingCETPactivity has been explored as a therapeutic target to raise HDL cholesterol levels and potentially reduce cardiovascular risk.

Methodological and Statistical Constraints

Research into CETP and lipid levels, particularly through genome-wide association studies (GWAS), faces inherent methodological and statistical limitations. Many studies acknowledge that their findings require replication in independent cohorts and functional validation to confirm true genetic associations and mitigate the risk of false positives, especially given the extensive multiple testing involved in GWAS.^[5] The power to detect modest genetic effects can be limited by sample sizes, with some studies indicating sufficient power only for variants explaining 4% or more of phenotypic variation.^[6] Furthermore, the reliance on imputation for unmeasured variants introduces potential error rates, which, while often low (e.g., 1.46–2.14% per allele), can still influence the accuracy of identified associations.^[1] The complexity of these studies means that reported statistical significances and estimated effect sizes must be interpreted cautiously, particularly when p-values are not rigorously adjusted for multiple comparisons, potentially leading to an overestimation of effects.^[7] While meta-analyses combine data from multiple cohorts to increase power, the overall proportion of variance explained by identified genetic variants for traits like HDL cholesterol, LDL cholesterol, and triglycerides remains relatively small (e.g., 7.4–9.3%).^[4] This highlights a significant “missing heritability” gap, where a substantial portion of genetic influence on lipid phenotypes is yet to be discovered, necessitating larger sample sizes and improved statistical power for comprehensive gene discovery.^[4]

Generalizability and Phenotypic Nuances

A notable limitation in many genetic studies of CETP and lipid traits is the restricted ancestry of study populations, predominantly focusing on individuals of European descent.^[8]This narrow demographic focus significantly limits the generalizability of findings to other ethnic groups, where genetic architecture and allele frequencies may differ, potentially influencing disease susceptibility and treatment responses.^[9] While some research has begun to include multiethnic cohorts, such as those comprising Chinese, Malays, and Asian Indians.^[4] the overall representation of global diversity remains a challenge for comprehensive understanding.

Phenotypic measurements also present complexities. The calculation of LDL cholesterol using formulas like Friedewald, particularly with imputation for missing values in cases of high triglycerides, introduces potential variability or error.^[4]The exclusion of individuals on lipid-lowering therapies from some analyses, or the imputation of untreated lipid values in others, aims to isolate genetic effects but may impact sample size or the representativeness of the studied population.^[4] Furthermore, variations in data processing, such as log-transforming triglycerides or averaging traits across multiple examinations, are necessary for robust analysis but underscore the careful consideration required when comparing results across diverse studies.^[8]

Environmental Interactions and Remaining Knowledge Gaps

The interplay between genetic variants and environmental factors represents a significant yet often unexplored area of limitation in understanding CETP’s role in lipid metabolism. Genetic variants can influence phenotypes in a context-specific manner, with environmental factors potentially modulating their effects; however, many studies do not undertake comprehensive investigations of gene-environment interactions.^[6]For instance, the impact of diet, lifestyle, or other exogenous factors on lipid levels in genetically predisposed individuals is largely unaccounted for, leaving critical gaps in fully explaining the observed phenotypic variation.

Beyond environmental influences, a complete understanding of the mechanisms by which CETPvariants affect lipid levels and their downstream health consequences remains an active area of research. While associations between genes and their protein products are often statistically robust, the precise functional implications of many identified single nucleotide polymorphisms (SNPs) are not always fully elucidated.^[5]The question of whether a gene polymorphism predisposing to an intermediate phenotype, such as HDL cholesterol levels, truly predicts the long-term risk of diseases like coronary heart disease, highlights a fundamental knowledge gap that requires further investigation.^[3] Addressing these complexities through functional studies and broader systems-level analyses is crucial for translating genetic associations into clinical insights.

Variants

The regulation of lipid metabolism, particularly the levels of high-density lipoprotein cholesterol (HDL-C), is a complex process influenced by numerous genetic factors. Variants within or near genes such as_CETP_, _HERPUD1_, _DELEC1_, _TNC_, and _SCARA5_contribute to individual differences in lipid profiles and, consequently, to cardiovascular health. Understanding the roles of these genes and their associated single nucleotide polymorphisms (SNPs) provides insight into the intricate pathways governing cholesteryl ester transfer protein activity and overall lipid homeostasis.

The _CETP_gene encodes cholesteryl ester transfer protein, a crucial player in reverse cholesterol transport, which facilitates the transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins and LDL. This protein significantly influences HDL cholesterol levels, with variants in_CETP_ often showing strong associations with circulating HDL-C concentrations.^[1] For instance, the A allele of rs3764261 , a variant near _CETP_, has been associated with an increase of 2.42 mg/dl in HDL cholesterol levels.^[1] While rs247616 , rs12720922 , and rs117427818 are also recognized variants in the _CETP_ region, they can affect _CETP_expression or activity, thereby modulating the balance of lipoproteins and influencing cardiovascular risk.

The _HERPUD1_ gene plays a key role in endoplasmic reticulum-associated degradation (ERAD), a cellular pathway responsible for the quality control of proteins. This process ensures that misfolded proteins are identified and degraded, maintaining cellular health. The variant rs247616 , located within or near _HERPUD1_, may influence the efficiency of this protein quality control system, potentially affecting the proper folding and degradation of other proteins involved in lipid metabolism.^[4] Such an indirect influence could impact the stability or activity of enzymes like _CETP_ or other lipid-processing proteins, thereby contributing to variations in an individual’s lipid profile and overall metabolic health.^[10] The genes _DELEC1_ and _TNC_ are involved in fundamental cellular processes, with _DELEC1_ contributing to cell adhesion and signaling, and _TNC_ (Tenascin C) being an extracellular matrix protein important for tissue structure and remodeling. The variant rs7029844 , found in this genomic region, may alter the expression or function of these genes, which can have broader implications for tissue integrity and cellular communication.^[4] Changes in these processes could indirectly affect the vascular environment, influencing inflammation and cellular interactions that are pertinent to lipid handling and the overall context in which _CETP_ functions.^[8] The _SCARA5_ gene encodes Scavenger Receptor Class A Member 5, a protein involved in recognizing and internalizing various molecules, including modified lipoproteins and cellular debris. As a scavenger receptor, _SCARA5_ contributes to the clearance of potentially harmful substances from circulation and plays a role in cellular immunity.^[11] Variants such as rs2726951 and rs28588017 could modify the activity or expression of _SCARA5_, thereby impacting the uptake of oxidized LDL or other lipids. Alterations in _SCARA5_ function can influence cholesterol efflux, inflammatory responses, and the overall lipid environment, which in turn may affect the efficacy of _CETP_ in reverse cholesterol transport and contribute to dyslipidemia.^[4]

Key Variants

RS ID	Gene	Related Traits
rs7029844	DELEC1, TNC	blood protein amount cholesteryl ester transfer protein measurement
rs247616	HERPUD1 - CETP	high density lipoprotein cholesterol measurement lipoprotein-associated phospholipase A(2) measurement coronary artery disease HDL cholesterol change measurement, response to statin phosphatidylcholine 34:3 measurement
rs12720922 rs117427818	CETP	triglyceride measurement total cholesterol measurement high density lipoprotein cholesterol measurement esterified cholesterol measurement, high density lipoprotein cholesterol measurement metabolic syndrome
rs2726951 rs28588017	SCARA5	blood protein amount cholesteryl ester transfer protein measurement

Definition and Physiological Function

Cholesteryl ester transfer protein (CETP) is a crucial plasma glycoprotein involved in the dynamic exchange of lipids between various lipoprotein particles in human circulation. Its primary function is to facilitate the transfer of cholesteryl esters from high-density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins, such as low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), in exchange for triglycerides.^[4] This enzymatic activity plays a pivotal role in the reverse cholesterol transport pathway, a process essential for removing excess cholesterol from peripheral tissues and returning it to the liver. Consequently, CETP activity significantly influences the plasma concentrations of HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides, thereby impacting overall lipid metabolism and cardiovascular health.^[3]

Genetic Basis and Associated Polymorphisms

The CETPgene encodes the cholesteryl ester transfer protein, and common genetic variations within this gene, particularly single nucleotide polymorphisms (SNPs), are recognized as significant determinants of an individual’s lipid profile.^[3] These CETP gene polymorphisms serve as genetic markers that can predispose individuals to specific intermediate phenotypes, such as altered plasma levels of HDL-C.^[3] Research has demonstrated that these variations are associated with differences in HDL-Cconcentrations and can influence the risk of conditions like coronary artery disease.^[3] The frequency and impact of these genetic predispositions can vary across different ethnic populations, as observed in studies on Japanese populations.^[3]

Clinical Relevance and Measurement of Lipid Traits

The activity of CETP and the presence of specific CETPgenetic variants hold substantial clinical relevance due to their strong association with dyslipidemia and the risk of cardiovascular disease (CVD) and coronary artery disease (CAD).^[3] Alterations in CETP function, often influenced by genetic background, can lead to unfavorable lipid profiles, particularly affecting HDL-C levels, which are considered an intermediate phenotype in the pathogenesis of CVD.^[6]For diagnostic and research purposes, associated lipid traits such as total cholesterol (TC),HDL-C, LDL-C, and triglycerides (TG) are precisely measured using enzymatic methods, often with clinical chemistry analyzers.^[2] Crucial operational definitions for these measurements include collecting blood samples after an overnight fast and accounting for confounding factors like medication use or diabetic status, which are essential for accurate phenotypic assessment in genome-wide association studies.^[2]

CETP and its Role in Cholesterol Metabolism

CETP(cholesteryl ester transfer protein) is a key enzyme involved in the intricate metabolic pathways that regulate plasma lipid levels. Its primary function is to mediate the transfer of cholesteryl esters from high-density lipoprotein (HDL) to apolipoprotein B-containing lipoproteins, such as very low-density lipoprotein (VLDL) and low-density lipoprotein (LDL).^[12] Concurrently, CETPfacilitates the reciprocal transfer of triglycerides from VLDL and LDL back to HDL, thereby playing a critical role in the remodeling of lipoprotein particles. This bidirectional lipid exchange significantly influences the composition and cholesterol-carrying capacity of these lipoproteins, impacting the overall cholesterol homeostasis in the body.

This molecular function of CETP is central to reverse cholesterol transport, a process where excess cholesterol is removed from peripheral tissues and transported back to the liver for excretion. By transferring cholesteryl esters from the “good” cholesterol (HDL) to lipoproteins that can deliver cholesterol to tissues (LDL), CETP activity can reduce HDL-cholesterol levels.^[3] Therefore, CETP is a critical biomolecule that directly influences the balance between cholesterol efflux and influx, with systemic consequences for lipid profiles.

Genetic Influences on CETP Expression and Lipid Profiles

The regulation of CETPactivity and expression is significantly influenced by genetic mechanisms. Common single nucleotide polymorphisms (SNPs) within theCETPgene have been identified as important genetic markers associated with variations in plasma high-density lipoprotein cholesterol (HDL-C) levels.^[3] These genetic variations can affect CETP gene expression patterns or the function of the resulting CETP protein, leading to altered lipid metabolism. For instance, specific CETP gene polymorphisms are linked to changes in circulating CETPprotein levels, which in turn modulate the efficiency of cholesteryl ester transfer.

Such genetic predispositions contribute to an individual’s lipid profile, establishing CETP as a gene whose variants can predict the risk of certain diseases.^[3] Genome-wide association studies (GWAS) have consistently identified loci in or near the CETPgene that influence lipid concentrations, including HDL-C, and are associated with the risk of coronary artery disease (CAD).^[4]Understanding these genetic mechanisms provides insight into the polygenic nature of dyslipidemia and the genetic basis of cardiovascular health.

CETPin Systemic Lipid Homeostasis and Cardiovascular Health

The systemic impact of CETPactivity extends beyond lipoprotein remodeling to influence overall lipid homeostasis and cardiovascular health. HighCETPactivity typically correlates with lower HDL-cholesterol levels, which is generally considered an unfavorable lipid profile associated with an increased risk of coronary artery disease (CAD).^[3] Conversely, reduced CETP activity or genetic variants that lead to lower CETP levels are often associated with elevated HDL-C and a potentially protective effect against CAD.^[3] This highlights CETP as a crucial determinant of the balance between protective and atherogenic lipoproteins circulating throughout the body.

Disruptions in CETP-mediated lipid transfer can therefore lead to homeostatic imbalances in plasma lipid concentrations, contributing to dyslipidemia. The interplay between CETP and other lipid-modifying enzymes affects the systemic distribution of cholesterol and triglycerides, influencing their availability to various tissues and organs. Consequently, CETPrepresents a significant target in the pathophysiological processes underlying cardiovascular disease, with its modulation offering potential therapeutic avenues for managing lipid disorders.

Interplay with Other Lipid-Modifying Pathways

CETP’s role in lipid metabolism is not isolated but is intricately linked with other key proteins and enzymes that collectively maintain lipid homeostasis. For instance, lecithin-cholesterol acyltransferase (LCAT) is an enzyme that esterifies free cholesterol in HDL, a process that provides the cholesteryl esters thatCETP subsequently transfers.^[4] Similarly, phospholipid transfer protein (PLTP) also influences lipoprotein remodeling by facilitating phospholipid transfer, affecting HDL particle size and composition, and thereby indirectly impactingCETP substrates and activity.^[4]These interactions form a complex regulatory network essential for proper lipoprotein function.

Furthermore, the expression and activity of genes involved in lipid metabolism, including CETP, can be influenced by various regulatory elements and transcription factors. For example, hepatocyte nuclear factor 4 alpha (HNF4A), a nuclear receptor, is essential for maintaining hepatic gene expression and lipid homeostasis, and its dysfunction can affect plasma cholesterol metabolism.^[4] Other proteins like apolipoprotein CIII (APOC3) also play a role in modulating triglyceride metabolism and lipoprotein catabolism, and variations inAPOC3 can confer a favorable plasma lipid profile, further illustrating the interconnectedness of these pathways.^[13] This complex regulatory network underscores how disruptions in one component, such as CETP, can have ripple effects across the entire lipid metabolic system.

Regulation of Lipid Metabolism and Flux

Cholesteryl ester transfer protein (CETP) is a pivotal enzyme in modulating plasma lipid concentrations, primarily by mediating the transfer of cholesteryl esters from high-density lipoproteins (HDL) to apolipoprotein B-containing lipoproteins, such as very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL), in exchange for triglycerides.^[3] This bidirectional lipid exchange is fundamental for the remodeling of lipoproteins and the overall flux of cholesterol within the reverse cholesterol transport pathway, where cholesterol is transported from peripheral tissues back to the liver. The activity of CETP significantly influences HDL-cholesterol levels, with higher CETP activity generally correlating with lower HDL-cholesterol and vice-versa, thereby affecting the overall lipid profile.^[3] The function of CETP is intricately linked to a network of other lipid-modifying enzymes and proteins that collectively maintain metabolic balance. Lecithin-cholesterol acyltransferase (LCAT), for example, is essential for the esterification of cholesterol within HDL particles, generating the cholesteryl ester substrates that CETP then transfers.^[4]Similarly, lipoprotein lipase (LPL) and hepatic lipase (HL) are critical for the hydrolysis of triglycerides and phospholipids, respectively, influencing the availability of substrates and the characteristics of acceptor particles for CETP-mediated lipid exchange.^[4] This complex interplay, also involving phospholipid transfer protein (PLTP) which further impacts HDL remodeling, underscores the integrated and dynamic nature of lipoprotein metabolism and cholesterol flux in the body.

Transcriptional and Post-Translational Control of Lipid Homeostasis

The precise regulation of proteins involved in lipid metabolism, including those pathways influenced by CETP, occurs through sophisticated transcriptional and post-translational mechanisms. Key transcriptional regulators like hepatocyte nuclear factors (HNF), specifically HNF4alpha and HNF1alpha, are indispensable for controlling hepatic gene expression and maintaining overall lipid homeostasis.^[4] These factors can modulate the synthesis of various lipoproteins and enzymes that either interact with CETP or are affected by its activity, thereby influencing systemic lipid levels. Another crucial regulator is sterol regulatory element-binding protein 2 (SREBP-2), which plays a role in linking isoprenoid and adenosylcobalamin metabolism, consequently impacting cholesterol biosynthesis via enzymes such as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR).^[1]Beyond transcriptional control, post-translational modifications and alternative splicing provide additional layers of regulation for metabolic pathways. For example, common single nucleotide polymorphisms (SNPs) in theHMGCR gene, which encodes the rate-limiting enzyme in cholesterol synthesis, have been observed to affect the alternative splicing of its exon 13, leading to variations in LDL-cholesterol levels.^[9] Such regulatory mechanisms are vital for adapting to changing metabolic demands, controlling enzyme activity, protein stability, and cellular localization to precisely manage the flux of lipids and maintain metabolic equilibrium.

Interplay with Cellular Signaling Networks

Lipid metabolism is not an isolated biochemical process but is deeply interconnected with broader cellular signaling networks that orchestrate responses to internal and external cues to maintain systemic homeostasis. While the researchs does not extensively detail direct signaling pathways initiated by CETP itself, its activity and the resulting changes in lipoprotein profiles profoundly influence and are influenced by various intracellular cascades. For instance, mitogen-activated protein kinase (MAPK) cascades are fundamental intracellular signaling pathways involved in crucial cellular processes such as growth, proliferation, and stress responses, and their activation can be modulated by specific lipid species or indirectly affect the expression of lipid-related genes.^[6] Furthermore, signaling pathways involving cyclic AMP (cAMP) and phosphodiesterase 5 (PDE5A) are known to regulate a diverse range of cellular functions, including the activity of vascular smooth muscle cells and potentially aspects of lipid uptake or synthesis in certain cellular contexts.^[6] These intricate signaling events can indirectly impact the cellular demand for cholesterol or the processing of lipoproteins, thereby establishing complex feedback loops that influence the overall lipid environment in which CETP operates and exerts its effects.

Systems-Level Integration and Disease Pathophysiology

The intricate regulation of lipid metabolism necessitates extensive pathway crosstalk and network interactions, with CETP playing a substantial role in maintaining systemic lipid balance. Genetic variations, such as specific single nucleotide polymorphisms likers19359809 in the CETPgene, are consistently associated with altered high-density lipoprotein cholesterol (HDL-C) levels and are recognized to influence the risk of coronary artery disease, underscoring CETP’s critical involvement in complex polygenic dyslipidemia.^[3]These genetic predispositions, in combination with various environmental and lifestyle factors, contribute to the emergent properties observed in individual lipid profiles, which can either confer protection against or promote the development of cardiovascular disease.

Dysregulation of CETP activity, whether stemming from genetic factors, acquired conditions, or pharmacological interventions, can severely disrupt the delicate balance of lipoprotein remodeling, leading to altered lipid concentrations that contribute to disease pathogenesis. For example, reduced CETP activity often results in elevated HDL-C, a phenotype that has been extensively investigated for its potential protective effects against atherosclerosis. Conversely, the body often employs compensatory mechanisms involving other lipid-modifying proteins or transcriptional regulators in an attempt to restore lipid homeostasis in response to primary dysregulation.^[4]A comprehensive understanding of these integrated mechanisms is crucial for identifying potential therapeutic targets aimed at managing dyslipidemia and mitigating associated cardiovascular risks.

Genetic Influence on Lipid Metabolism

Polymorphisms within the cholesteryl ester transfer protein (CETP) gene play a significant role in influencing plasma lipid profiles, particularly high-density lipoprotein cholesterol (HDL-C) levels. Genetic variations, such as single nucleotide polymorphisms (SNPs) likers3764261 , rs1864163 , and rs9989419 , are strongly associated with circulating HDL cholesterol concentrations.^[1] Understanding these genetic associations can provide diagnostic utility by identifying individuals with genetically determined variations in lipid metabolism, which may predispose them to specific dyslipidemias.^[3] Such insights can contribute to a more comprehensive assessment of an individual’s metabolic health beyond standard lipid panels.

Risk Stratification and Prognostic Value for Cardiovascular Disease

Genetic polymorphisms in CETPare important in assessing an individual’s predisposition to and prognosis for coronary heart disease (CHD). Research indicates that specificCETP gene polymorphisms, which predispose to an intermediate phenotype of lipid levels, can predict the risk of developing CHD.^[3] This prognostic value allows for improved risk stratification, helping to identify high-risk individuals who might benefit from targeted prevention strategies or more aggressive management. Incorporating CETPgenetic information into risk assessment models could enhance personalized medicine approaches, moving beyond traditional risk factors to better anticipate disease progression and long-term cardiovascular outcomes.

Clinical Utility in Patient Management

The genetic information related to CETP holds potential for various clinical applications, including guiding treatment selection and monitoring strategies for lipid-lowering therapies. Genetic testing for CETP polymorphisms could assist clinicians in tailoring interventions, especially in populations where these genetic markers have been extensively studied, such as Japanese populations where associations with HDL-C have been identified.^[3] By understanding an individual’s CETP genotype, healthcare providers may better anticipate treatment response and monitor the efficacy of lipid-modulating interventions, ultimately optimizing patient care and potentially mitigating complications associated with dyslipidemia.

References

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[6] Vasan, R.S. et al. “Genome-wide association of echocardiographic dimensions, brachial artery endothelial function and treadmill exercise responses in the Framingham Heart Study.”BMC Med Genet, 2007.

[7] Benyamin, Beben, et al. “Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels.”American Journal of Human Genetics, vol. 84, no. 1, 2008, pp. 60-65.

[8] Aulchenko YS et al. “Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts.” Nat Genet. 2008 Dec;40(12):1428-31. PMID: 19060911

[9] Burkhardt, R. et al. “Common SNPs in HMGCR in micronesians and whites associated with LDL-cholesterol levels affect alternative splicing of exon13.” Arterioscler Thromb Vasc Biol, 2008.

[10] Gieger C et al. “Genetics meets metabolomics: a genome-wide association study of metabolite profiles in human serum.” PLoS Genet. 2008 Nov 28;4(11):e1000282. PMID: 19043545

[11] Wallace C et al. “Genome-wide association study identifies genes for biomarkers of cardiovascular disease: serum urate and dyslipidemia.” Am J Hum Genet. 2008 Jan;82(1):139-49. PMID: 18179892

[12] Havel, R. J., and J. P. Kane. “Structure and Metabolism of Plasma Lipoproteins.” McGraw-Hill, 8th ed., New York, 2005, chap. 114.

[13] Pollin, Timothy I., et al. “A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection.” Science, vol. 322, no. 5904, 2008, pp. 1087-1092.